Hi Ron,

It seems there are a variety to drug targets in PD. It's all too complex for me without studying hard, and I'd rather read Darkly Dreaming Dexter!

Here's the discussion from the article I posted about gabapentin (I'm not sure if it's accessible to the general public):

Discussion

It has been long recognized that degeneration of the substantia nigra is a causative factor for Parkinson's disease[12] related to loss of dopaminergic supply to the striatum and that levodopa given to patients with parkinsonism is metabolized to dopamine with beneficial effect on the symptoms.[13]

To date the principal treatments of parkinsonism have been oriented to dopaminergic supply.[14] It is known that dopamine from the substantia nigra acting at the striatum[15] results in an inhibitory cascade that is GABAergic from caudate, putamen, and globus pallidus externa.[16]

Gabapentin, (1-aminomethyl)-1-cyclohexaneacetic acid, was synthesized as a structural analogue of GABA.[17] However, gabapentin does not act at GABAA, GABAB,[18] or GABAC[19] receptors, is not metabolized into GABA or a GABA agonist,[20] does not inhibit GABA uptake[21] nor degradation by GABA-transaminase,[22] but it is known to be a competitive inhibitor of branched-chain amino acid aminotransferase and stimulates the activity of glutamate dehydrogenase.[22]

It is known that gabapentin increases brain GABA,[23, 24] enhances the release of GABA from rat neostriatum,[25] and inhibits monoaminergic release from the striatum, but not acetylcholinergic release from the striatum.[26]

Further, gabapentin does not act at benzodiazepine, glutamate, glycine, Image-methyl-d-aspartate receptors,[27] nor does it influence sodium or calcium channels.[28, 29] It is not a substrate for any of the enzyme systems involved in the synthesis or catabolism of GABA.[22]

In neurons, the gabapentin-binding site[30] is associated with Image-neutral amino acid transporter[31] on cell bodies.[32]

We chose a dose of 400 mg three times a day because we noted that a dose of 300 mg three times a day in other patients with parkinsonism has little or no effect. The 11-day washout period was chosen because in a companion study[33] we noted that subjects with spinal cord injury did not return to baseline for at least a week after cessation of gabapentin despite a half life (t1/2) of 4 to 6 hours.[34]

In this trial, 400 mg gabapentin administered TID improved the total Unified Parkinson's Disease Rating Scale score, suggesting that gabapentin exerts an effect on the symptoms and signs of parkinsonism.

In addition, subjects taking gabapentin manifested improvement in their Unified Parkinson's Disease Rating Scale activities of daily living subscore over placebo therapy, documenting a benefit on the subjective symptoms of Parkinsonism. Because gabapentin has been anecdotally reported to benefit patients with essential tremor,[10] we elected to look at gabapentin effects on parkinsonism tremor.

Of interest, even when those measures of tremor in the Unified Parkinson's Disease Rating Scale were removed from analysis, the total Scale scores still demonstrated a significant response to drug. Heretofore, this improvement in nontremor signs and symptoms of parkinsonism has been observed only with administration of dopamine receptor agonists.

These study results are the first evidence of significant treatment benefit by an agent having no known cholinergic or dopaminergic effect in parkinsonism. However, since all subjects were taking at least one dopaminergic agent, we cannot rule out a synergistic effect between gabapentin and the concurrent dopaminergic drug(s).

The failure of gabapentin to demonstrate a statistically significant effect on the examination scale of the Unified Parkinson's Disease Rating Scale may be due to the design of the trial itself. The last dose of drug, placebo or gabapentin, was noon of the day of evaluation, and the evaluation was between 4 PM and 6 PM, about 4 to 6 hours after the dose.

Gabapentin t1/2 is 4 to 6 hours, which suggests that subjects may have waning of effect. Thus, gabapentin likely affects the examination subscale of the Unified Parkinson's Disease Rating Scale, but to document this the evaluation should occur 1 to 3 hours after the dose, not 4 or more hours afterward.

We were interested in the possible effects of gabapentin on parkinsonism tremor, so we analyzed a number of measures of this effect. Three items in the Unified Parkinson's Disease Rating Scale (16, 20, and 21) and one item in the Webster scale (6) measure tremor effects. Tremor activity in the electromyography can be recorded with surface electrodes. While there seemed to be some improvement in each of these measures when subjects took gabapentin, none of the effects reached statistical significance.

All subjects had advanced parkinsonism, at least Hoehn and Yahr stage 2.5. Fourteen subjects had response fluctuations to their prescribed dopaminergic agents, but we collected “off” and “on” time activities of daily living data in only 7 subjects. Because meaningful results could not be obtained, we did not analyze our data for “off” or “on” effects.

The brevity of the study limited risks that may accrue in long-term treatment with antiparkinsonism medications.[35, 36, 37, 38] It also restricts conclusions regarding long-term efficacy and tolerability. Since parkinsonism is a lifelong illness once manifest, an investigation of long-term effects is needed. We have observed that some patients have received continued undiminished benefit from gabapentin for more than a year.

Although the mechanism of action of gabapentin still remains elusive, it seems to increase brain GABA,[24] including striatal GABA,[23] and to increase GABA release and acetylcholine release while reducing other monoaminergic release.[26]

Gabapentin also doubles postsynaptic GABA potentials, an effect blocked by GABAA-receptor inhibition.[39] GABAA receptors are known to be prominent in the striatum, globus pallidus interna, and substantia nigra reticulata[40] whereas GABAB receptors are more commonly seen in the substantia nigra compacta.[41] All of the GABA receptors are expressed in the thalamus.

Since parkinsonism is associated with relatively increased function of the indirect inhibitory GABAergic pathway, improvement in the condition may result from stimulation of GABAA receptors with the immediate feedback to inhibit further GABA release.[25] Alternatively, if the striatal indirect GABAergic pathway is involved, action of GABA on the globus pallidus interna and substantia nigra reticulata will decrease inhibition of target thalamic neurons and increase mobility.

Since striatal GABA-mediated postsynaptic inhibitory activity is an action in concert with the action of the dopamine on the striatum in the indirect pathway,[42] this may explain the effect of gabapentin on parkinsonism. Regardless, additional work to elucidate the mechanism of action of gabapentin as an adjunctive medicine in parkinsonism needs to be done.

One final note of caution seems pertinent. While this study did not analyze the effect of gabapentin on specific forms of parkinsonism, we have observed that 5 of 6 patients with progressive supranuclear palsy, who had not been subjects of this study, had worsening of their disease when given gabapentin, becoming bedfast (Hoehn and Yahr stage 5). Fortunately, this is a reversible effect on stopping the gabapentin. This observation suggests that not all forms of parkinsonism will benefit from gabapentin.